The present invention is directed to methods and formulations for treating migraines, muscle sprains, muscle spasms, spasticity, tension headache, tension-related migraines and related conditions associated with muscle tension and pain.
Migraine headaches are a debilitating condition in which some 53 million persons per year suffer acute pain. Frequently, migraine is accompanied by sickness and vomiting and a sensitivity to light and noise.
Several theories on the pathogenesis of migraine have been hypothesized and include: i) the vascular theory (i.e., migraine is a vasospastic disorder that is initiated by vasoconstriction in the cranial vasculature); ii) the cortical spreading depression theory (i.e., CSD begins with a brief wave of excitation, followed by a prolonged period of neuronal depression, which is associated with disturbances in nerve cell metabolism and regional reductions in blood flow); iii) the neurovascular hypothesis (i.e., migraine triggers or CSD can activate trigeminal nerve axons, which then release neuropeptides, such as substance P, neurokinin A, and CGRP) from axon terminals near the meningeal and other blood vessels that produce an inflammatory response in the area around the innervated blood vessels); iv) the serotonergic abnormalities hypothesis (i.e., proposes that serotonin may be involved in the pathogenesis of migraine due to observations that both plasma and platelet levels of serotonin fluctuate during a migraine attack, an initial surge in plasma serotonin levels may cause constriction of cerebral blood vessels and a reduction in cerebral blood flow. If the blood flow is sufficiently reduced, migraine aura may result); and v) the integrated hypothesis (i.e., triggers such as stress, glare, noise, the patient's internal clock, the dilation of the internal or external carotid arteries, or other factors may activate specific centers in the brain stem causing migraine).
Muscle sprains, muscle spasms, spasticity, tension headaches and tension-related migraines are also common debilitating conditions that are associated with acute pain, chronic pain and involuntary movement that can be so severe that the condition(s) frequently disrupt an individual's daily life.
Muscle spasm may occur as a result of direct soft tissue trauma with spasm of injured muscles. It may also arise as a consequence of spinal nerve root irritation from musculo-skeletal injury. Para spinal muscles are primarily affected in this situation, so called “cervical and lumbar sprains.” Muscle spasm can manifest as a sudden involuntary contraction of one or more muscle groups and is usually an acute condition associated with muscle strain (partial tear of a muscle) or sprain (partial or complete rupture of a ligament). Spasticity is a state of increased muscular tone with exaggeration of the tendon reflexes from an upper motor neuron (brain or spinal cord) injury in which spinal inhibitory processes are suppressed or lost. The result is chronic, severe spasm of the muscles of the extremities hindering function and causing pain. Spasticity is often associated with illnesses such as multiple sclerosis, stroke and spinal cord injury. Tension headaches and tension-related migraines are a result of over activity of muscles of the scalp, forehead and neck.
Ergot is the product of a fungus that grows most predominantly on rye with other grains being affected. Since the discovery of ergot and ergot alkaloids over four hundred years ago, the cumulative results of many diverse studies have indicated that ergot alkaloids play a significant role in the functioning of the mammalian body. For example, the pharmacological effects of ergot alkaloids on the uterus, cardiovascular system, smooth muscles and vasculature have been studied.
Ergot alkaloids pharmacological actions are complex due to their effects on several different receptors. However, clinical applications for ergot alkaloids have been studied in various disease states and medical conditions, e.g., Parkinson's disease and post-partum hemorrhage. One particular area where the therapeutic use of ergot alkaloids has received particular attention is in the treatment of migraines.
Ergot alkaloids have been used for treating migraines since the 1920s and their continued use for the acute relief of moderate or severe migraine is still being studied today. The ergot alkaloids possess varied and complex pharmacological actions due to there ability to act as partial agonists or antagonists at 5HT1 and 5HT2 receptors as well as adrenergic, dopaminergic and tryptaminergic receptors. The spectrum of their effects depends upon the agent(s), dosage, species, tissue, and experimental or physiological conditions. It is because of the ergot alkaloids multiple pharmacological effects on the various receptors that their exact mechanism of action for treating migraine is uncertain.
In the prior art, ergot alkaloids have been used for the local treatment of various disease states and conditions.
For example, U.S. Pat. No. 4,916,132 to Seibel describes dihydroergotamine compositions and methods of preparing the same for use in the local treatment of trophic disturbances, e.g., stasis dermatoses, ulcers and tissue death.
Additionally, U.S. Published Patent Application No. 2002/0042438 to Pelletier et al. describes a method of reducing or inhibiting the glycation of skin proteins, in particular, for preventing or treating the signs of ageing of the skin and/or the orange-peel appearance of the skin and for slimming and/or refining the silhouette and contours of the face, by topically applying a composition containing an ergothioneine or derivative thereof to the skin of a person.
As with the ergot alkaloids, many diverse studies utilizing serotonin (5 hydroxytryptamine, 5-HT) have indicated that serotonin plays a significant role in the functioning of the mammalian body, both in the central nervous system and in peripheral systems as well. Morphological studies of the central nervous system have shown that serotonergic neurons, which originate in the brain stem, form a very diffuse system that projects to most areas of the brain and spinal cord. R. A. O'Brien, Serotonin in Mental Abnormalities, 1: 41 (1978); H. W. M. Steinbusch, HANDBOOK OF CHEMICAL NEUROANATOMY, Volume 3, Part II, 68 (1984); N. E. Anden, et al., Acta Physiological Scandinavia, 67: 313 (1966). These studies have been complemented by biochemical evidence that indicates large concentrations of 5-HT exist in the brain and spinal cord. H. W. M. Steinbusch, supra.
Serotonin (5-hydroxytryptamine, 5-HT) is said to play a key role in regulating the vascular tone, and serotonin deficiency is said to result in a vasodilatation causing the migrainous headache. The onset of action is affected via 5-HT1-receptors in the region of the vascular walls of cerebral arteries.
Accordingly, in the last few years, the chemical structure of serotonin has been modified in various manners, resulting in changes of the pharmacological properties. For example, indole derivatives were synthesized which cause the cerebral vessels to be selectively tonizised (contracted) combined with a rapid improvement of the symptoms. These are so-called serotonin agonists having a particular affinity for 5-HT1-receptors.
The class of serotonin agonists having a particular affinity for 5-HT1 receptors are typified, for example, by sumatriptan, zolmitriptan, naratriptan, and rizatriptan to name a few. Oral bioavailability is an important factor in the efficacy of a drug and one that may account for consistency of response with repeated use. Sumatriptan tablets have a low oral bioavailability (14%). All of the second-generation triptans have improved bioavailability (rizatriptan and zolmitriptan, 40-45%; naratriptan, close to 70%). Sumatriptan, rizatriptan, and zolmitriptan are metabolized by the MAO system. All of these compounds, however, have some adverse effects which require supervised administration at efficacious doses. PHYSICIAN'S DESK REFERENCE, (48th ed., 1994).
In the prior art, there have been previous attempts to provide for a more efficacious and safe treatment using serotonin agonists specific for the treatment of 5-HT1 receptor subtype.
For Example, U.S. Pat. No. 5,863,935 to Robertson et al. describes certain compounds having “5-HT1-like” receptor agonist properties and their administration in a number of ways, including topical or intranasal application.
Additionally, U.S. Pat. No. 5,805,571 to List, describes a transdermal therapeutic system for the systemic administration of active substances wherein at least one of the active substances listed is a serotonin agonist of the group comprising indole derivatives. Typically, transdermal systems are not used in acute situations because they do not provide an immediate effect, but rather provide prophylaxis or prolonged effect. Transdermal systems such as that described in the '571 patent to List require a period of time for the drug to pass through a barrier layer and onto/into the skin which may take e.g., a substantial period of time until the dose of drug that is absorbed is sufficient to alleviate the pain associated with the headache.
Skeletal muscle relaxants have played a significant role in alleviating stiffness, pain, and discomfort caused by muscle sprains, muscle spasms, spasticity, tension headache and tension-related migraines. Their mechanism of action can be attributed to their direct effect on skeletal muscles (e.g., direct acting skeletal muscle relaxants such as dantrolene) or their ability to reduce spasticity by increasing pre-synaptic inhibition of motor neurons, inhibiting monosynaptic or polysynaptic reflexes at the spinal level (e.g., centrally acting skeletal muscle relaxants such as tizanindine and baclofen).
Most skeletal muscle relaxants are centrally acting and are administered via the oral route or parenteral route. The drawback of the oral or parenteral administration is that there are frequent systemic side effects such as fatigue, lethargy, weakness and mental clouding, particularly as higher doses are reached. Benzodiazepines, e.g., diazepam, have additional drawbacks such as tolerance, psychological dependency and withdrawal effects, e.g., seizures. Oral administration route also entails delay of drug effect through gastrointestinal absorption and systemic circulation.
In certain instances skeletal muscle relaxants can also be administered topically. For example, U.S. Pat. No. 5,364,628 to Kissel et al. describes a transdermal adhesive plaster or patch containing tizanidine for application every three days for the systemic treatment of rheumatic pains and muscle spasms. Also, UK Patent Application No. 2098865 to Joachim Franz et al. describes a composition and method for administering a sustained release micro emulsion containing tizanidine. A suitable dose of 10-50 mg of tizanidine may be administered, which provides an effect for up to three (3) days. Although topical administration has been described in the art, FDA approval has only been granted for oral and parenteral administration of skeletal muscle relaxants.